The present invention relates to lipid-based nitric oxide donors and more particularly to lipids having one or more of the following groups: (a) S-nitroso groups, (b) O-nitroso-groups, and (c) N-nitroso groups.
Nitric oxide can be used therapeutically in a number of ways. At high concentrations, nitric oxide is cytotoxic and may be used to reduce the numbers of undesirable cells, such as cancer cells, bacterial cells and cells present in atherosclerotic lesions. At lower concentrations, nitric oxide may promote the health of certain cells and tissue.
Compounds that contain S-nitroso groups, O-nitroso-groups, and N-nitroso groups are all known to release nitric oxide.
O-nitroso compounds are compounds having one or more xe2x80x94Oxe2x80x94NO groups, and are also referred to as O-nitrosylated compounds and nitrite compounds.
S-nitroso compounds are compounds with one or more xe2x80x94Sxe2x80x94NO groups and are also referred to as nitrosothiols and S-nitrosylated compounds. An xe2x80x94Sxe2x80x94NO group is also referred to in the art as a sulfonyl nitrite, a thionitrous acid ester, an S-nitrosothiol or a thionitrite.
Compounds having an xe2x95x90Nxe2x80x94NO group are referred to herein as N-nitroso compounds. Common examples are compounds having xe2x80x94Nxe2x80x94N2O2xe2x88x92 groups (see structure below), which are known in the art as nonoate compounds, and more specifically as N-nonoate compounds.
Examples of the above three classes of compounds can be found, for example, in U.S. Pat. Nos. 5,583,101 and 5,814,666, the entire disclosures of which are hereby incorporated by reference.
U.S. Pat. No. 5,824,669 and WO 00/49993, which are herein incorporated by reference, describe nitrosated and nitrosylated steroids. Further information can be found within these documents.
U.S. Pat. No. 5,767,089 (the ""089 patent), the disclosure of which is hereby incorporated by reference, discloses among other things nitroxide-labeled macromolecules, including hemoglobin, albumin, immunoglobulins and liposomes. See, e.g., Abstract and Col. 1, lines 13 et seq. For further information, see the disclosure of the ""089 patent (see, also, U.S. Pat. Nos. 5,824,781 and 5,741,893).
The present invention is directed to a new class of S-nitrosylated, N-nitrosylated and/or O-nitrosylated lipid molecules.
According to an embodiment of the invention, novel nitric-oxide releasing lipid molecules are provided which comprise a lipid molecule selected from (a) phosphoglycerides, (b) lipids having a sphingosine base as a backbone, (c) monoacylglyerols, (d) diacylglycerols, (e) glycosylacylglycerols, and (f) sterol compounds of the formula: 
where R is a branched aliphatic chain of eight or more carbon atoms, wherein the lipid molecule is provided with a nitric-oxide containing group, which comprises (a) a xe2x80x94Sxe2x80x94Nxe2x95x90O moiety, (b) a xe2x80x94Oxe2x80x94Nxe2x95x90O moiety, or (c) a 
moiety.
Preferred lipids having a sphingosine base as a backbone include N,N,N-trimethylsphingosine and sphingolipids, such as gangliosides. Preferred phosphoglycerides include phosphatidylinositol and phosphatidylcholine. Cholesterol is a preferred sterol molecule. A preferred 
moiety is the 
moiety and more preferably the 
moiety.
The pharmaceutical compositions comprising the nitric-oxide releasing lipid molecules of the present invention contain varying amounts of the lipid molecules, for example, at least 0.001 wt %, at least 0.01 wt %, at least 0.1 wt %, at least 1 wt %, at least 10 wt %, or at least 90 wt %.
In other embodiments of the invention, methods of forming a nitric oxide releasing lipid molecule is provided. These methods comprise:
(1) providing a lipid molecule having a nucleophilic moiety selected from a thiol moiety, an amine moiety and an alcohol moiety, the lipid molecule selected from (a) phosphoglycerides, (b) lipids having a sphingosine base as a backbone, (c) monoacylglyerols, (d) diacylglycerols, (e) glycosylacylglycerols, and (f) sterol compounds of the formula: 
xe2x80x83where R is a branched aliphatic chain of eight or more carbon atoms; and
(2) supplying the lipid molecule with a nitric-oxide containing group at a position corresponding to the nucleophilic moiety, wherein the nitric-oxide containing group comprises a xe2x80x94Sxe2x80x94Nxe2x95x90O moiety, a xe2x80x94Oxe2x80x94Nxe2x95x90O moiety, or 
moiety.
In many preferred embodiments of the invention, an alcohol moiety on the lipid molecule is converted to a group comprising a thiol moiety before supplying the lipid molecule with the nitric-oxide containing group, which can be, for example, a nitric-oxide containing group comprising an xe2x80x94Sxe2x80x94Nxe2x95x90O moiety.
In some embodiments, the nitric-oxide releasing lipid molecules of the present invention are provided in a topical liquid, such as a solution, dispersion, spray, lotion, gel, cream or ointment.
Other embodiments are directed to a drug delivery system comprising a medical article and the nitric-oxide releasing lipid molecules of the present invention. Preferred medical articles include (a) a bandage or a patch and (b) an intravascular medical device, such as a balloon catheter, an injection catheter, an infusion catheter, a stent, a stent graft, or a distal protection device.
The nitric-oxide releasing lipid molecules associated with the drug delivery system can be, for example, (a) provided within a polymer matrix, preferably a biocompatible matrix selected from a stable polymer matrix and a biodegradable polymer matrix, (b) dissolved or dispersed in a solution, (c) adsorbed on a tissue-contacting surface of the medical article, or (d) provided within a micelle or a liposome.
The drug delivery system in some embodiments will further comprise a therapeutically effective amount of an auxiliary therapeutic agent, such as an agent having antineoplastic activity, an agent having antiproliferative activity, or an agent having both antineoplastic and antiproliferative activity.
According to another embodiment of the present invention, a method for therapeutically administering nitric oxide to a patient is provided. The method comprises administering the nitric-oxide releasing lipid molecules of the invention to a patient. Preferred routes of administration include (a) topical administration routes, (b) administration routes in which the nitric-oxide containing lipid molecules are administered within the body, for example, by implantation, via an intravascular delivery device (e.g., a balloon catheter, an injection catheter, an infusion catheter, a stent, a stent graft, or a distal protection device) or via a direct injection route.
According to other embodiments of the invention, methods of treating or preventing various conditions are provided. These methods comprise administering an amount of the nitric-oxide releasing lipid molecules of the invention effective to treat or prevent the condition. Preferred conditions include atherosclerosis, myocardial infarction, restenosis, peripheral vascular disease, stroke, impotence, septic shock, arthritis, cancer, bacterial infection, impetigo, epidermolysis bullosa, eczema, neurodermatitis, psoriasis, pruritis, erythema, hidradenitis suppurativa, warts, diaper rash, and jock itch.
In other embodiments of the invention, the nitric-oxide releasing lipid molecules are used to promote wound healing in a patient or to reduce the cells present in an atherosclerotic lesion in a patient.
One advantage of the present invention is that nitric oxide releasing compounds with lipophilic or amphiphilic characteristics are provided.
Another advantage of the present invention is that nitric oxide releasing compounds are provided which can be readily incorporated into lipophilic tissue, promoting tissue uptake and enhancing tissue retention time.
Another advantage of the present invention is that nitric oxide releasing compounds are provided which can be readily incorporated into a cell membrane, promoting cell uptake and enhancing cell retention time.
These and other embodiments and advantages of the present invention will become readily apparent to those of ordinary skill in the art upon review of the description and claims to follow.